A randomized blinded phase II study of ompenaclid (RGX-202-01) vs placebo in combination with FOLFIRI plus bevacizumab (BEV) in patients (pts) with previously treated RAS mutated (RASmt) advanced/metastatic colorectal cancer (mCRC)

Pts with RASmt mCRC have a short median progression-free survival (PFS) of ∼5–6 months and median overall survival (OS) of ∼1 year after failing first-line (1L) therapy. Novel therapies with modes of action distinct from these established agents are urgently needed to improve on patient outcomes. Creatine metabolism was found to be activated in RASmt mCRC as a mechanism to fuel the increased energy demands of RASmt tumors. Ompenaclid is a first-in-class small molecule inhibitor of the creatine transporter SLC6A8 that prevents import of creatine and the high energy metabolite phosphocreatine, which results in depletion of intracellular ATP levels, leading to tumor cell apoptosis. In an open-label single arm study (RGX-202-001) as 2L treatment in pts with RASmt mCRC, ompenaclid at 2400 mg and 3000 mg orally twice-daily (BID) in combination with FOLFIRI/BEV was shown to have potential clinical benefit with a tolerable safety profile (ESMO 2023, abstract 646P).
Trial design
Key eligibility criteria: measurable disease per RECIST v1.1, disease progression after 1L oxaliplatin-based therapy and ECOG performance status 0–1. Treatment consists of FOLFIRI/BEV (irinotecan intravenously [IV] 180 mg/m2, 5-FU 46-hour IV 2400 mg/m2, leucovorin IV 400 mg/m2, BEV IV 5 mg/kg every 2 weeks), with double-blind 1:1 randomization to either ompenaclid 3000 mg PO BID or placebo, stratified by prior exposure to 1L BEV. Treatment will continue until disease progression or unacceptable toxicity. Tumor assessment will be performed every 8 weeks. The primary end point is overall response rate. Secondary endpoints include PFS, OS, safety and tolerability. The study will enroll 70 pts and is conducted in Spain, Belgium and France. Study enrollment is ongoing.